For many years surgical tissue closure has been accomplished by a variety of fundamental techniques such as the use of clamps, staples or a variety of sutures. Disadvantages associated with use of those techniques has led to the development of new techniques for joining damaged mammalian tissues and reducing or preventing the loss of blood or other bodily fluids as well.
One approach has been the development of tissue adhesives for joining tissues, derived from either natural or synthetic products. Adhesive bonding with natural products such as fibrin or glues derived from mollusks such as mussels and barnacles has shown promise. Fibrin glue has been prepared by reacting a cryoprecipitate of fibrinogen and thrombin in the presence of calcium ion to produce fibrin monomer. This monomer reacts in the presence of a factor found in the patient's blood (Factor XIII) to form a polymer. These fibrin glues have found use in topical and spray applications as a hemostatic agent on bleeding anastomoses, bleed points caused by needle holes or suture lines, and on the heart surface to control bleeding. The fibrin glues have only a modest tensile strength and therefore have not found significant use for repairing tissues which are subjected to load.
Barnacle glue has shown promise since its polymerization is rapid and occurs under conditions which are similar to the environment in which they would be used. It also maintains its adhesive properties under adverse chemical conditions. However under typical use conditions the resulting adhesive joint has unacceptable tensile strength. Preparation of glues from mollusks is difficult however, and large quantities of material must be processed to obtain a significant amount of adhesive. To prepare 1 milligram of adhesive from barnacles requires the harvest and treatment of at least 150 barnacles.
For these reasons a great deal of attention has been given to the development of synthetic adhesive systems. Especially prominent has been the development of adhesive and hemostasis-inducing compositions comprising fast curing monomers such as dialkyl methylene malonates (U.S. Pat. No. 3,221,745) and monomeric lower alkyl 2-cyanoacrylates (U.S. Pat. Nos. 3,223,083 and 3,264,249). Because the lower alkyl 2-cyanoacrylates did not appear to combine the desired, if not necessary, properties of low toxicity and adequate adsorption by tissues, the use of alkoxyalkyl 2-cyanoacrylates was developed (U.S. Pat. No. 3,559,652). Other polymers presently under investigation include polyurethanes and epoxy resins. The latter two polymer systems suffer disadvantages of limited "pot life" or "open time", have significant exotherms when polymerized and exhibit toxicity to surrounding tissues.
It is advantageous for tissue adhesives to able to be absorbed or degraded in the body, otherwise known as bioabsorption or biodegradation. Among the advantages are that it has been shown that long-term implants of nondegradable films and disks in rodents will induce neoplasms, and although there are no studies to show this will occur in primates, it is a matter for concern. Second, it is obviously more desirable that a device used in vivo should only remain as long as necessary to ensure proper healing. This should reduce or prevent adverse tissue reactions and/or foreign body responses. In orthopedic applications absorbable pins and plates that could perform in place of metal implants would require only a single surgical procedure. Absorbable polymers would also be useful for use with implantable systems for long-term drug delivery. The absorption ability of current materials ranges from the least degradable materials such as ceramics and carbon fibers through metallic alloys to the most degradable, organic polymers having reactive chains.
Shalaby in Encyclopedia of Pharmaceutical Technology, Swarbrick and Boylan, eds., Marcel Dekker Inc., New York, 1988, pp. 465-476 has classified bioabsorbable polymers into three groups; soluble, solublizable and depolymerizable. Soluble polymers are water-soluble and have hydrogen-bonding polar groups, the solubility being determined by the type and frequency of the polar group(s). Solublizable polymers are usually insoluble salts such as calcium or magnesium salts of carboxylic or sulfonic acid-functional materials which can dissolve by cation exchange with monovalent metal salts. Depolymerizable systems have chains that dissociate to simple organic compounds in vivo under the influence of enzymes or chemical catalysis.
The response of tissues to biodegradable materials is dependent on the rate of absorption, but more importantly it is regulated by the toxicity of the degradation products. Thus it is important to have controlled absorption to decrease the toxicity and reaction of surrounding tissue to products that do elicit a response. It also is important to ensure that the mechanical properties of the polymer are maintained for sufficient time to allow proper healing. Thus absorbable polymeric adhesives and the products of their bioabsorption must be compatible with the surrounding tissues.
2-cyanoacrylates bond rapidly and form strong adhesive joints. Their properties may be modified easily by modification of their substituent groups. They are well-suited for biological applications since, unlike other adhesives such as epoxy resins and polyurethanes, 2-cyanoacrylates may be used as pure monofunctional monomers having well-defined properties. They homopolymerize rapidly at room temperature in the presence of weakly basic moieties such as water and other weakly basic species present in bodily fluids. Since their introduction in 1958 they have found use in many surgical applications such as hemostasis, as sealants, for retrofilling and as general tissue adhesives. A 2-cyanoacrylate suitable for use as a tissue adhesive should be non-toxic and biodegradable, should wet and spread on tissue substrates and polymerize quickly to a thin. polymeric film. The polymeric adhesive should have a degree of flexibility, especially when bonding soft tissues. Biodegradability is especially important because the adhesive should be replaced by the body's tissues and not slow or bar complete healing.
In the homologous series of poly(alkyl 2-cyanoacrylates) the lower homologs such as the methyl ester exhibit the highest rate of bioabsorption but also elicit the greatest tissue response. They also do not wet, spread or polymerize on biological substrates as rapidly as the higher homologs. On the other hand, the higher alkyl esters such as the isobutyl ester elicit minimal tissue reaction but degrade slowly if at all. Therefore the main drawbacks for use of the alkyl 2-cyanoacrylates has been their histotoxicity and/or lack of biodegradability. Despite those deficiencies, the n-butyl and isobutyl and other higher esters have been found acceptable as tissue adhesives. In an effort to combine the higher biodegradability of the lower alkyl esters with the lower toxicity of the higher esters Banitt and Nelson (U.S. Pat. No. 3,559,652) developed alkoxyalkyl 2-cyanoacrylate adhesives which were stated to be bioabsorbable and to exhibit minimal toxicity and inflammation. Kronenthal and Schipper (U.S. Pat. No. 3,995,641) developed a carboxyalkyl 2-cyanoacrylate which was stated to be useful as an adhesive or a wound dressing.
Other problems which have been observed with alkyl 2-cyanoacrylate adhesives are their low monomer viscosities and the formation of a high modulus crust on soft tissues. Due to their low molecular weight and rapid polymerization times 2-cyanoacrylates may be formulated with biologically acceptable modifiers. Because the monomer initiates with any anionic or free radical source, formulations with modifiers are not easily made. Control of the viscosity of the monomeric adhesive may be obtained by adding a biologically acceptable thickening agent. Millet has reported that polylactic acid is an effective thickening agent (Structural Adhesives: Chemistry and Technology, S.R. Hartshorn ed., Plenum Press, New York, 1986, pp.249-303)
Plasticizers are commonly used to decrease the brittleness of polymers. Plasticizers function by lowering the glass transition temperature and the modulus of the polymer. Plasticizers may be internal or external. Internal plasticization is accomplished by using mixtures of compatible monomers to form a copolymer having segments of varying hardness. External plasticization may be obtained by the addition of esters such as cyanoacetates, malonates, adipates, sebacates and the like (Millet, op. cit.).
Therefore it is clear that there is a need for tissue adhesives which have been modified by plasticizers/modifiers which exhibit biodegradability, an acceptable histotoxicity and reasonably match the modulus of the tissues being joined by the adhesive.